CA1059131A - Preparation of n-2-(6-hydroxybenzothiazolyl)-n-phenyl (or substituted phenyl) ureas - Google Patents

Abstract

Title PREPARATION OF N-2-(6-HYDROXYBENZOTHIAZOLYL)-N'-PHENYL (OR SUBSTITUTED-PHENYL) UREAS

Abstract N-2-(6-hydroxybenzothiazolyl)-N'-phenyl(or substituted-phenyl)ureas of the formula FORMULA I

wherein R is hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy or halo are prepared by reacting 2-amino-6-hydroxy-benzothiazole with 1-2 moles of phenyl (or a sub-stituted phenyl) isocyanate and then hydrolysing any 6-phenylcarbamoyloxy compound thus produced to the corresponding 6-hydroxy derivative.
These compounds are useful as immune regulants and anti-viral compounds.

Description

Background of the Invention Heterocyclic ureas such as N-benzimidazolyl, N-benzothiazolyl or N-benzoxazolyl-N'-phenyl ureas are useful as immune regulants and anti-viral compounds according to Paget et al., J. Med. Chem., 12, 1010 (1969); 1016 (1969). These N-heterocyclic-N'-phenyl ureas can be substituted in either the phenyl moiety of the heterocyclic benzothiazole, benzoxazole or benzimidazole ring with substituents such as halo, alkoxy, alkyl, carboethoxy, trifluoromethyl, nitro and the like, or in the N'-phenyl group with substituents such as chloro, fluoro, nitro, methyl, trifluoromethyl, bromo and the like. Compounds which contain a hydroxy group as a substituent in the phenyl : -1- X-4358 .., ~, ', ,' , ', ' .,. '~' . .
.,, '', ,' '' , , ~.' ~ ", '., '' ~' ' ' ''"'~'' ' ' '' ' " 1059131 portion of the heterocyclic nucleus have not been prepared.
Obvious methods of preparing such a 6-hydroxy derivative have been found not to be operative; for example, the corresponding 6-methoxy compound is not readily demethylated by the use of 50 percent HBr or other standard demethylating reagent. In addition, carrying out the standard synthesis of benzimidazolyl, benzoxazolyl or benzothiazolyl ureas involying the reaction of an isocyanate with a 2-amino-substi~uted benzimidazole, benzoxazole or benzothiazole, having a benzyloxy substituent in the phenyl moiety of the heterocyclic ring also did not provide an operative procedure for preparing the corresponding hydroxy compound since the benzyl group proved to be extremely re- '-sistant to debenzylation using hydrogenation conditions in-volving a palladium catalyst. N-2-(6-hydroxybenzothiazolyl)-N'-phenyl urea was, however, discovered as a metabolic product in urine when the corresponding 6-methoxy compound , was fed to rats. A complex procedure for preparing this compound involvin~ the use of trimethylsilyl ch'loride has been devised, aS fully set forth in the copending Canadian application of Paget and Wikel, Serial No. 233,027 filed August 7, 1975.
It is an object of this invention to provide an im- ', proved method for preparing N-2-(6-hydroxybenzothiazolyl)-N'- `~
phenyl (or substituted-phenyl) ureas, which improved method is more adaptable to industrial produ,ction than methods heretofore available and which avoids thé use of expensive reagents.
Summary of the Invention In fulfillment of the above and other objects, this invention provides a method for the preparation of N-2-(6-hydroxybenzothiaZolyl)-N'-phenyl (or substituted phenyl) ureas represented by formula I below which comprises the reaction

-2- ~-4358 , lOS9~31 of 1-2 moles (up to a 100 percent molar excess) of a phenyl-isocyanate (R'-C6H4-NCO) with 2-amino-6-hydroxybenzothiazole to produce a reaction mixture containing a 6-carbamoyloxy derivative (structure II) and permissably, some of the com-pound of structure I below.

I R' R~NH--CO--O~S R ' -NH-CO-NH~--~,'..
II

The N-2-(6-phenylcarbamoyloxybenzothiazolyl)-Ni-phenyl urea (II) thus produced is treated with base in an inert solvent at a temperature below about 100C. until all of the 6-phenyl-carbamoyloxy group of the benzothiazolyl urea has been ~ -hydrolyzed to provide a compound of structure I. The 6- ~
20 phenylcarbamoyl compound produced in the isocyanate reaction ~ -can be hydrolyzed to the 6-hydroxy derivative either in the original reaction mixture or during an initial separation step wherein advantage is taken of the phenolic character of the 6-hydroxy group to dissolve it in base. The base-insoluble compound is separated and then hydrolyzed by the process of this invention. It is, of course, preferable to carry out the hydrolysis step in the unseparated reaction mixture. ~-The 6-hydroxy urea (I) already present or produced by the hydrolytic reaction is not adversely affected under the specified hydrolysis reaction conditions.

_3_ X-4358 - , , -In structures I and II abo~ve, R' is the same group in each instance and can be hydrogen, halo, (Cl-C3) alkyl or (Cl-C3) alkyloxy. The term "(Cl-C3) alkyl" includes methyl, ethyl, _-propyl and isopropyl. Thus, the term "(Cl-C3) alkyloxy" includes methoxy, ethoxy, n-propoxy and isopropoxy. The term "halo" includes fluoro, chl~ro, bromo and iodo.
In the reaction between the phenylisocyanate (R'-C6H4-NC0) and the ?-amino-6-hydroxybenzothiazole, the 2-amino group of the benzothiazolyl reacts far more rapidlythan does the 6-hydroxy group. Thus, with a single mole of phenylisocyanate, the predominant reaction product will be -N-2-(6-hydroxybenzothiazolyl)-N'-phenyl urea. The reaction between the hydroxy group and the phenylisocyanate does, how-ever, proceed at a measurable reaction rate. Using only a single mole of isocyanate, therefore, the chief reaction -product will be the urea of structure I, as stated above but there will also be present 2-amino-6-carbamoyloxybenzothiazole, N-2-(6-carbamoyloxybenzothiazolyl)-N'-phenyl urea and unreacted 2-amino-6-hydroxybenzothiazol starting material. Sufficient phenylisocycnate or substituted phenylisocyanate should be employed to insure that all of the 2-amino group of the ben-zothiazole reacts to form the corresponding urea, and pre- -ferably, a stoichiometric excess from about 25-100 percent of the isocyanate is employed. A greater than 100 percent stoi-chiometric excess (2 moles per mole of amino benzothiazole) is, of course, not necessary since with 2 moles of phenyl (or a substituted-phenyl) isocyanate present, all of the benzothiazole will be converted to the 6-carbamoyloxy urea (structure II
above). If less than 2 moles, but more than 1 mole, of iso-_4_ X-4358 s , ,~ , ,. , "i , ": ` ' ' ': . . ` .

lOS9131 cyanate is used per mole of benzothiazole, the reaction mix- -ture will contain both the 6-hydroxy and 6-carbamoyloxy derivatives. In any case, in order to obtain a substantially quantitative yield of the desired 6-hydroxy compound, it is necessary to hydrolyze any 6-carbamoyloxy derivative produced in the isocyanate reaction using base in an inert`solvent at a temperature below about 100C. until substantially all of the 6-carbamoyloxy group is hydrolyzed to the desired 6-hydroxy compound of structure I above. Useful inert solvents include water and the lower alkanols including methanol and ethanol.
Suitable bases for use in the process include alkali metal hydroxides such as potassium or sodium hydroxide; alkali metal alcoholates such as potassium ethylate, sodium methylate and the like; alkali metal carbonates including potassium and sodium carbonate: and ammonium hydroxide, and substituted ammonium hydroxides such as triethyl ammonium hydroxide, trimethyl ;
ammonium hydroxide and the like. The temperature of the reaction is customarily carried out at the reflux temperature of the solvent; i.e., from 65C. for methanol to 100C. for ;
water. As will be apparent to those skilled in the art, the higher the reflux temperature, the shorter the time needed for the hydrolysis to proceed to completion. Like-wise, the solubility of the base in the inert solvent in an important consideration with the alkali metal hydroxides, -for example, being more soluble than the carbonates. Use of the hydroxides therefore requires less reaction time than use of the carbonates. Complete hydrolysis of the 6-phenylcar-bamoyloxy compound usually requires from 1 to about 18 hours :

_5_ X-4358 .. . .
. .

~\

depending upon qolvent, base and temperature employed, and upon the nature of the 6-phenyl (or substituted-phenyl) car-bamoyloxy ~roup.
The character of the isocyanate (R'-C6H4-NC0) affects not only the rate of hydrolysis of the 6-phenyl (or substituted-phenyl ? carbamoyloxy group as indicat'ed above, but also affects the ratios of the various products of the reaction of the particular isocyanate with 2-amino-6-hydroxy-benzothiazole, specially the rate of urea formation compared to the rate of reaction with the 6-hydroxy group.
N-2-(6-hydroxybenzothiazolyl)-N'-phenyl urea and other substituted phenyl ureas represented by formula I
above are useful as anti-viral agents and as immune sup- --pressants, as set forth in the copending Canadian application of Paget and Wikel, Serial No. 233,027, filed August 7, 1975.
The preparation of N-2-(6-hydroxybenzothiazolyl)-N'-phenyl urea is illustrated in the examples which follow with Examples 2-6 describing alternate methods of hydrolyzing the 6-phenylcarbamoyloxy group. ¦ -Example 1 A slurry of 152 g. of 2-amino-6-hydroxybenzothiazole was prepared in 3 liters of acetone. A solution of 109 g. of phenylisocyanate in 150 ml. of acetone was added thereto in `
dropwise fashion. After the addition had been completed, the ; -reaction mixture was heated at refluxing temperature over-night. The reaction mixture was cooled to about 50C. and decolorizing charcoal added. The mixture was filtered, and a second batch of 109 g. of phenylisocyanate in acetone added to the filtrate. The mixture was again heated to refluxing temperature for about 2 hours, and was cooled. A white solid ,,.; .

comprising N-2-(6-phenyl-carbamoyloxybenzothiazolyl)-N'-phenyl urea formed in thç above reaction precipitated. The precipitate was separated by filtration, and the filter cake washed with acetone. Yield = 73 percent.
Melting point above 250C.
Analysis for C21H15N4O35 Calc.: C, 62.52; H, 3.75; N, 13.89;
S, 7.95;
Found: C, 62.30; H, 3.97; H, 13.69;
S, 7.76.
Four grams of the above N-2-~6-carbamoyloxybenzo-thiazolyl)-N'-phenyl urea were dissolved in 150 ml. of an-hydrous methanol.- A 10 percent slurry of 0.5 g. of sodium methylate in methanol was added with stirring. The reaction mixture was stirred at room temperature overnight. Thin layer chromatography showed that about 50 percent of the carbamoyloxy group had been removed by hydrolysis. The reaction mixture was then slowly heated, and the progress of the reaction continually checked by thin layer chromatography. After two hours of heating at about 45C., the hydrolysis was sub- ~
20 stantially 100 percent complete. The reaction mixture was ;~ -then cooled and carefully acidified to pH=4 with 10 percent aqueous hydrochloric acid. N-2-(6-hydroxybenzothiazolyl)-N'- ~-phenyl urea formed in the above rèaction was separated by filtration. The filter cake was washed with methanol and then ether. Examination of its NMR spectra indicated that a phenyl-carbamoyloxy group was no longer present in the molecule. This fact was further substantiated by shifts in the ultraviolet spectrum upon solution of the compound in acid and base. N-2-(6-hydroxybenzothiazolyl)-N'-phenyl urea thus prepared had the .

lOS913~
following characteristics: m.p. above 250C.; mass spectral fragments at 285,?12, 192, and 166; pKa = 10.9 ~66% DMF).
Analysis Calc. for C14HllN3O2S: C, 58.93; ~, 3.89;
N, 14.73;
Found,: C, 58.34; H, 3.76;
' N, 13.~6.
Exam~le 2 A reaction mixture was prepared containing 100 mg.
of N-2-(6-phenylcarbamoyloxybenzothiazolyl)-N'-phenyl urea, 100 mg. of sodium methylate and 25 ml. of methanol. The reaction mixture was refluxed for one-half hour, at the end of which time thin layer chromatography indiCated that none of the starting material was present and that the product of the reaction was the corresponding 6-hydroxy com- -pound. Further refluxing of the reaction mixture for 18 hours showed no decomposition of N-2-~6-hydroxybenzothiazolyl)- ~' N'-phenyl urea,formed in the reaction. ,,-Example 3 Example 2 was repeated except that 20 mg. of po~
20 tassium hydroxide were substituted for the sodium methylate ''-of that example. An examination of the reaction mixture by ' thin layer chromatography after 6 hours indicated that the ,' hydrolysis of the 6-phenyl-carbamoyloxy group was incomplete. ~' Refluxing was continued for another 12 hours, at the end of which time it was ascertained that hydrolysis was complete and that the starting material had been entirely converted to the corresponding 6-hydroxy compound. ,, ,', :

ao ., A`

Example 4 The procedure of Example 1 was repeated except that about 35 mg. of potassium carbonate were employed in place of the sodium methylate of that example. Examination of the reaction mixture at intervals indicated that 18 hours were required to hydrolyze completely the 6-phenylcarbamoyloxy group.
Example 5 The procedure of Example 3 was repeated except that 25 ml. of water were employed in place of the methanol of that example. The reaction mixture was heated slowly, and the solid starting material went into solution at about 80C. Refluxing for one hour gave complete hydrolysis of the 6-phenylcarbamoyloxy group.
Example 6 The procedure of Example 2 was repeated except that 0.35 ml. of triethylamine were used in place of the sodium methylate of that example. Examination by thin layer chromatography indicated that the hydro:lysis was complete after a 6-hour reflux.

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Claims (4)

The embodiments of the invention in which an ex-clusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula FORMULA I

wherein R is hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy or halo characterized by reacting 2-amino-6-hydroxy-benzo-thiazole with from 1 to 2 moles of a phenyl isocyanate of the formula FORMULA II

wherein R is as defined above; hydrolyzing any thus-obtained 6-carbamoyloxy compound of the formula FORMULA III
wherein R is as defined above with a base of the group consisting of alkali metal hydroxides and carbonates, ammonium hydroxide and (C1-C2) alkyl-substituted ammonium hydroxides in an inert solvent at a temperature not higher than about 100°C.

2. A compound of Formula I as defined in Claim 1, when prepared by the process of Claim 1 or an obvious chemical equivalent thereof.

3. A process as in Claim 1 for preparing N-2-(6-hydroxybenzothiazolyl)-N'-phenyl urea which comprises reacting 2-amino-6-hydroxybenzothiazole with phenyliso-cyanate in acetone at reflux temperature and reacting the resulting compound with sodium methylate in methanol.

4. N-2-(6-Hydroxybenzothiazolyl)-N'-phenyl urea when prepared by the process of Claim 3 or by an obvious chemical equivalent thereof.